Purification of vitamin



Patented June I, 1948 Y 4 UNITED STATES PATENT OFFICE PURIFICATION OF VITAMIN Be Malcolm L. Brown, Clark Township, Union County, N. 5., assignor to Merck & Co., Inc., Rahway, N. 5., a corporation of New Jersey No Drawing. Application February 11, 1947, Serial No. 727,945

7 Claims. 260-297.5)

1 2 This invention is concerned generally with desired. The aqueous solution containing the processes for preparing substantially pure vitacrude vitamin is adjusted to a pH of between 6.7

min Be from solutions containing small amounts and 7.5 by the addition of an alkaline material, of the vitamin or from impure dry preparations such as sodium carbonate. This solution is reof the vitamin. More particularly it relates to 5 acted with boric acid and the resulting solution is the preparation of a pharmaceutical grade of ordinarily allowed to stand at room temperature high quality vitamin B6 from low assay vitamin for a period of time of about 24 to 48 hrs,

preparations which cannot be purified by reduring which time the vitamin Be-borate complex crystallization from Water, ethanol, or other precipitates. Cooling to 0 0., the employment solvents, 10 of seed crystals, and agitation all accelerate the It is now discovered that vitamin B6 can be crystal zati n p ss- A q a t tat v yield f separated in substantially pure form and in the vitamin Bs-borate complex has been obtained almost quantitative yield directly from crude vitathree hours after adding the boric acid. In min preparations containing as low as general, the precipitation rate depends on the vitamin Be. This is accomplished by reacting 15 original purity of the vitamin B6, that is, the the crude vitamin, in aqueous solution, with boric higher the assay of the crude material, the faster acid to form the relatively insoluble borate comthe precipitation. The pH at which the complex plex of vitamin B6 which crystallizes, is recovered is formed may V ry over a ran e of from about in substantially pure form by filtration and is 6.7 to 7.5, although it is preferred to employ a reconverted to pure vitamin B6 by reaction with 0 pH between 6.8 and 7.0. 7

an aliphatic alcohol. These reactions may be The precipitate which forms is recovered by chemically represented as follows: filtration or centrifugation and washed. The

V CH2OH OHKO7BTOOHI noon on 1131303 1120 n+ noon 0 0 onion snio -on3 0G: H3O g V lnon 1 v wherein R is an alkyl radical, and HA is a mineral precipitate is then'reacted with a lower aliphatic acid. alcohol, preferably under acidic conditions, as

Although the boratecomplex of vitamin B6 has 40 for example, with a solution of hydrogen chloride been prepared previously, it was not realized that in methanol, a solution of hydrogen bromide in this complex would be an excellent method of ethanol, 2. solution of sulfuric acid in propanol, purifying the vitamin, nor was any method known and the like, thus decomposing the borate complex for recovering vitamin B6 from said complex. It and producing a salt of vitamin B6, admixed with is particularly unexpected that it is possible to trialkyl borate. The trialkyl borate is convencrystallize the borate complex of vitamin B6 in iently separated from this mixture by distillation; substantially pure form, directly from an aqueous the residual substantially pure salt of vitamin solution of a vitamin preparation which is so Bo can be isolated as such or if desired can be impure that vitamin B6, itself, cannot be crystalconverted by conventional methods to vitamin lized therefrom. Ba base. If desired the complex can be de- It is ordinarily preferred to carry out this novel composed by reaction with a lower alphatic and improved process using crude vitamin prepalcohol alone, but under these conditions the arations assaying between 59% and 94% vitamin reaction proceeds more slowly since the acidic Be although preparations assaying from about conditions accelerate the decomposition. The 20% up to nearly 100% may be employed, if complex is also decomposed by boiling with aqueous alkali; however, the free vitamin base is not very stable in hot aqueous solution, and the decomposition is usually carried out by treatment with an alcoholic mineral acid solution. Although any lower aliphatic alcohol may be used in the decomposition of the borate complex,

it is ordinarily preferred to employ methanol,

since methanol forms the low-boiling trimethyl borate which is most readily separated from vitamin B6. Thus when the vitamin Bs-borate complex is treated with methanolic hydrogen chloride there is obtairieda mixture of Vitamin B5 hydrochloride and trimethyl borate. Thismixture is then distilled to' remove the volatile trimethyl borate and the residue is washed with ethanol and filtered to produce substantially pure Exampl 5 .1 em o vitam n Bshydroch or de sa g 6% is dis olved in 5.0 cc o w te to whio is added. approxim t l 13-2 si s.- o sodi m bonate. The yellow colored solution is filtered and the insoluble material is washed with 10 cc. of water. 6 gms. ofboric acid is added to the lear filtr e, whi h cau s the sol on t becom i ky. o ortions o wate of 5 soea h are hen added hu p oduc n a c ea olution-r i l t on s al w d to tanda oom tem e a ur for two ay during which time h bo t o plex precipitates. The fine white solid precipitat wh h ha i rmsd is a te ed an as with 10 cc. of water, The weight of the dried precipitate is 33.6%v ins.

e d e m erial is treat d wiil122 m hanol and 30 cc. 7 N alcoholic The mixture is isii edand. on heatin white s arates. The still ion con nu d n l'm i of the solvent has distilled off. The distillation is repeated two more times using 225 cc. fresh methanol for each run, and the distillate tested for (CHaO) 3B. The residual vitamin B6 hydrochloride is slurried with cold ethanol, the resulting suspension filtered and the crystalline product washed with cold ethanol, and dried. Weight of the vitamin B hydrochloride product is 3'. g., assay 100%; yield 96.1%. This may be recrystallized if necessary to remove any ash which may be present. The pure vitamin B5 hydrochloride thus obtained can be convertedto sub stantially pure vitamin "B6 according to con-- ventional procedures.

Modifications may be made in carrying out the pr ent ve on without: departin from the, sp i d s pe thereof, a d the. invention s to be limited only by the appended claims.

I claim: i

1. The process of purifying vitamin B6, which comprises reacting impure vitamin B6 with boric acid to produce a vitamin Bea-borate complex, separating said complex in substantially pure form, decomposing said complex by treatment with a lower aliphatic alcohol, and recovering the purified vitamin B6.

2. The process of purifying vitamin B6, which comprises reacting impure vitamin Be With boric acid to produce a vitamin Bra-borate complex.

separating said complex in substantially pure form, reacting the substantially pure vitamin Bil-borate complex with a lower aliphatic alcohol under acidic conditions to produce the corresponding salt of vitamin B6 in substantially pure form, and recovering the purified vitamin B6.

3; The processwhich comprises reacting boric acid wit h an aqueous solution containing impure vitamin B6 to produce a vitamin Bs-borate complex, crystallizing the vitamin Bs-borate complex, in substantially pure form, directly from the aqueous reaction solution, reacting the substantially pure vitamin Bs-borate complex with a lower aliphatic alcohol solution of a mineral acid to produce a mixture containing the corresponding mineral acid salt, of vitamin B8 and trialkyl borate, separating the trialkyl borate from said mixture by distillation and recovering the substantially pure salt of vitamin B6.

4. The process which comprises reacting boric acid with an aqueous solution containing impure vitamin Be, at apH of approximately 6.7 to 7.5, to produce avitamin Bis-borate complex, reacting the substantially pure vitamin Bs-borate complex with methanolic hydrogen chloride to produce a mixture of vitamin B6 hydrochloride and trimethyl boratascparating the trimethyl borate from said mixture by distillation, and recovcr ng'tho su stant a ly. p re tamin 5 ydrochloride.

5. "Ihe processwhic comprises treating a vitamin Bs-borate complex with a lower aliphatic alcohol to produce a mixture containing vitamin B5 and trialkyl borate, separating the trialkyl borate from said mixture by distillation, and recovering the vitamin Be:

6. The process which comprises reacting a vitamin Bs-borate complex with alower aliphatic alcohol solution of a mineral acid to produce a mixture containing the corresponding mineral acid salt of vitamin B6 and trialkyl borate, separating the trialkyl borate from said mixture by distillation and recovering said salt of vitamin B6.

'7. The process which comprises reacting a substantially pure vitamin Bs-borate complex with methanolic hydrogen chloride to produce a mixture containing vitamin B6 hydrochloride and trimothvl borate; separat n tho i n t orate from said mixture by distillation and recovering the subs antiall nurovitamin B ydr h r d 

